Biology subjects

Betancourt, R.

Publications and source records attributed to Betancourt, R..

3 recordsLinked to original sources

bioRxiv2020

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1 splice variant PGC-14, which regulates PPAR{gamma}-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPAR{gamma}inhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.

cancer biology↗

bioRxiv2019

Swimming motility and chemotaxis control the spatial organization, persistence, and inflammatory activity of a model intestinal pathobiont

Understanding the processes that spatially restrict resident gut bacteria and the mechanisms by which disease-causing pathobionts escape this control will open new avenues for microbiome-based therapies. Using live imaging and genetically engineered bacteria, we discovered that flagella-based swimming motility and chemotaxis enable a model Vibrio pathobiont to govern its own spatial organization within the larval zebrafish gut and to persist in the face of the disruptive forces of intestinal flow. Bacterial mutants lacking motility traits became aggregated and lumenally confined, making them susceptible to periodic expulsion from the host. Consequently, non-motile and non-chemotactic mutants experienced large fluctuations in absolute abundance and impaired interbacterial competition. Further, we found that motile bacterial cells induce expression of the proinflammatory cytokine TNF in gut-associated macrophages and the liver. Using inducible genetic switches, we demonstrate that swimming motility can be manipulated in situ to modulate the spatial organization, persistence, and inflammatory activity of gut bacteria.

microbiology↗

bioRxiv2019

Cryptococcus deuterogattii VGIIa infection associated with travel to the Pacific Northwest outbreak region in an anti-GM-CSF autoantibody positive patient in the United States

The Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington have been the location of an ongoing Cryptococcus gattii outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver three years earlier and Costa Rica four months prior to presentation. Phenotypic evidence shows the fungal mass isolated from the patients brain is C. gattii. In agreement with the phenotypic results, MLST provides genotypic evidence that assigns the infecting organism within in the C. gattii species complex and belonging to the C. deuterogattii VGIIa clade. Whole genome sequencing revealed >99.99% identity to the C. deuterogattii reference strain R265, indicating that the infecting strain is derived from the highly clonal outbreak strains in the PNW. We conclude the patient acquired the C. gattii infection during his travel to region three years prior and the infection was dormant for an extended period of time before causing disease. The patient tested positive for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, supporting earlier reports that implicate these autoantibodies as a risk factor a risk factor associated with C. gattii infection.\n\nImportanceMortality rates associated with C. gattii infections are estimated to be between 13% and 33% depending on an individuals predisposition, and C. gattii has caused more at least 39 deaths in the PNW region. There have been four other international travel cases reported in patients from Europe and Asia with travel history to the PNW, but this study describes the first North American travel who acquired C. deuterogattii infection presenting within the United States, and the first case of a C. deuterogattii outbreak infection associated with anti-GM-CSF autoantibodies. Early and accurate diagnoses are important for disease prevention, treatment, and control of infectious diseases. Continual reporting of C. deuterogattii infections is necessary to raise awareness of the ongoing outbreak in the PNW and alert travelers and physicians to the endemic areas with potential risks.

microbiology↗